ABSTRACT Alveolar macrophages (AMs) are central sentinels of the lung that function in pathogen clearance and initiation of inflammatory cascades. Molecular mechanism(s) coupling these two processes are not yet clear. Previous AM depletion studies show both beneficial and detrimental outcomes for pulmonary inflammation and injury, implying a more targeted approach is required for precise modulation of the AM behaviors. Our opportunity in fulfilling this unmet medical need is the identification of the role of TRIM72 in regulating AM phagocytosis and inflammatory signaling pathways. Our pull-down assay identified an interaction between TRIM72 and a novel phagocytic receptor and our data imply that TRIM72 may impact LPS sensing by TLR4. We hypothesize that TRIM72 shapes innate immunity of the lung by regulating CRIg phagocytosis and TLR4 signaling pathway. We aim to dissect the molecular mechanisms of such regulation in this exploratory grant in two specific aims: Aim 1: to delineate the mechanism(s) through which TRIM72 regulates pathogen clearance by AMs, and Aim 2: to explore the mechanism(s) of TRIM72 regulation on TLR4 and the effect of CRIg. Our results should lead to novel discovery on elucidating the role of AMs in pulmonary inflammation and injury and identify new targets for tailored modulation of AM function for the treatment of these lung diseases.